First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers.

Autor: Tang F; Genentech, Inc., South San Francisco, California, USA., Kunder R; Genentech, Inc., South San Francisco, California, USA., Chu T; Genentech, Inc., South San Francisco, California, USA., Hains A; Genentech, Inc., South San Francisco, California, USA., Nguyen A; Genentech, Inc., South San Francisco, California, USA., McBride JM; Genentech, Inc., South San Francisco, California, USA., Zhong Y; Genentech, Inc., South San Francisco, California, USA., Santagostino S; Genentech, Inc., South San Francisco, California, USA., Wilson M; Genentech, Inc., South San Francisco, California, USA., Trenchak A; Genentech, Inc., South San Francisco, California, USA., Chen L; Genentech, Inc., South San Francisco, California, USA., Ly J; Genentech, Inc., South San Francisco, California, USA., Moein A; Genentech, Inc., South San Francisco, California, USA., Lewin-Koh N; Genentech, Inc., South San Francisco, California, USA., Raghavan V; Genentech, Inc., South San Francisco, California, USA., Osaghae U; Genentech, Inc., South San Francisco, California, USA., Wynne C; Christchurch Clinical Studies Trust Ltd., New Zealand Clinical Research, Christchurch, New Zealand., Owen R; Genentech, Inc., South San Francisco, California, USA., Place D; Genentech, Inc., South San Francisco, California, USA.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2023 Sep; Vol. 16 (9), pp. 1653-1666. Date of Electronic Publication: 2023 Jul 23.
DOI: 10.1111/cts.13576
Abstrakt: Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively. Although GDC-2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug-induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC-2394 was rapidly absorbed; exposure increased in an approximately dose-proportional manner with low-to-moderate intersubject variability. The mean terminal half-life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high-fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC-2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole-blood stimulation assays showed rapid, reversible, and near-complete inhibition of the selected PD biomarkers, IL-1β and IL-18, across all tested doses. Despite favorable PK and target engagement PD, the GDC-2394 safety profile precludes its further development.
(© 2023 Genentech, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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